This invention relates to certain novel analogs of the naturally occurring prostaglandins, synthetic intermediates and processes employed in their preparation. In particular, it relates to novel 2-descarboxy-2-tetrazol-5-yl-15-substituted-.omega.-pentanorprostaglandins and N-acyl and N-sulfonyl 15-substituted-.omega.-pentanorprostaglandin carboxamides wherein the 15-substituent is (2-aryl)ethyl or (1,1-dimethyl-2-aryl)ethyl.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. Their structure, biological activities and medicinal use have been variously described in U.S. Pat. Nos. 3,971,826 and 3,984,400.
In the preparation of synthetic pharmaceutical agents, among one of the principle objects is the development of analogs of naturally occurring compounds which are highly selective in their physiological activity and which have an increased duration of activity. In a series of compounds like the naturally-occurring prostaglandins which have an extremely broad activity spectrum, increasing the selectivity of a single compound usually involves the enhancement of one physiological effect and the diminution of the others. By increasing the selectivity, one would, in the case of the natural prostaglandins, expect to alleviate the severe side effects, particularly the gastrointestinal effect frequently observed following systemic administration of the natural prostaglandins.
In order to achieve increased selectivity and duration of action in the 11-hydroxy prostaglandin series, many researchers have concentrated on the molecular modification of the last five carbons on the bottom side chain. One modification consists of removing one to four carbon atoms from the end of the lower side chain and terminating the chain with an aryl or heteroaryl group. Compounds of this type are described, for instance, in Belgian Patent No. 802,231 and in U.S. Pat. No. 3,984,424. Another modification of this portion of the bottom side chain consists of replacing some of the hydrogens attached to the last five carbon atoms with alkyl groups. Compounds of this type are, for instance, 16,16-dimethyl prostaglandin E.sub.2 and F.sub.2.alpha. which are described by B. J. Magerkin et al, Prostaglandins, 4, 143 (1973). Other researchers have concentrated on the molecular modification of the carboxylic acid group at the C-1 position of 11-hydroxy prostaglandins. Several of these modifications consist of converting the carboxylic acid group into an N-acyl or N-sulfonyl carboxamide or into a tetrazole. Compounds of the carboxamide type are described in U.S. Pat. No. 3,954,741 and compounds of the tetrazole type are described in U.S. Pat. No. 3,883,513.
These references describe the biological activities of the 11-hydroxy prostaglandins they disclose as being: hypotensive, bronchodilator, anti-fertility and in some cases anti-ulcer and anti-thrombogenic. Specifically, U.S. Pat. No. 3,984,424 states that the p-biphenyl esters of 17-aryl-.omega.-trisnorprostaglandins have potent anti-fertility activity.
In view of the prior art and biological tests of the compounds described therein, it has been surprisingly discovered that all members of the instant 15-substituted-.omega.-pentanor prostaglandins of the F series and the instant 15-substituted-.omega.-pentanor prostaglandins of the E series wherein the 15-substituted is 2-arylethyl all have potent anti-fertility activity while having diminished hypotensive and diarrheal activity. It further has been discovered that in view of the cited prior art, the instant 15-substituted-.omega.-pentanor prostaglandins of the E series wherein the 15-substituent is 1,1-dimethyl-2-arylethyl have potent anti-ulcer activity while having diminished hypotensive, diarrheal and smooth muscle activity.